Pharmacokinetic/pharmacodynamic analysis of β-amyloid response following modulation of the gamma secretase enzyme

Abstract

The amyloid hypothesis of Alzheimer's Disease asserts that β-amyloid (Aβ) plays a direct role in the pathogenesis of the disease. Modulation of the γ-secretase enzyme represents a potentially viable therapeutic approach to reduce the pathogenic species of Aβ. The objectives of the present study were (1): to establish in vitro-to-in vivo potency translation for a lead chemical series to aid in SAR understanding, and (2) to characterize the in vivo Aβx-42 lowering potencies of two tool compounds via pharmacokinetic/pharmacodynamic (PK/PD) modeling. Male Hartley guinea pigs received a single oral dose (30 mg/kg) of γ secretase modulators. Plasma, cerebro spinal fluid (CSF) and brain were harvested at 6 hours post dose for measurement of drug exposure and Aβ concentration. In addition, the time course of plasma drug concentration, plasma Aβ, CSF Aβ, and brain Aβ were measured in guinea pigs following oral administration of two tool compounds. An indirect response model with inhibition of Aβ production was used to characterize the PK/PD relationship. An in vitro-to-in vivo potency translation between total brain exposure and brain Aβx-42 was established for the lead chemical series in the guinea pig. Simple PK/PD analysis indicated that 50% reduction in brain Aβx-42 occurs at total brain or plasma exposure that are ˜ 73x or 13x of in vitro IC50. PK/PD modeling of the time course data showed that the in vivo free plasma IC25% for brain Aβx-42 were 5.19 and 41.7 nM for tool compounds 1 and 2, respectively. In addition, the free plasma IC25% for plasma and CSF Aβx-42 values for compound 1 were 3.22 and 3.25 nM, respectively. Preliminary human dose prediction indicates that doses of 225 mg BID and 28 mg BID are required for the two tool compounds to achieve a 25% reduction in brain Aβx-42 levels.. PK/PD analysis indicated (1) in vitro potency can be used to drive chemistry SAR and (2) higher potency compounds with improved ADME/PK properties are needed for optimal human dosing.